1. Field of the Invention
The present invention relates to cycloalkyl, cycloalkenyl, cycloalkylmethyl and cycloalkenylmethyl (2-hydroxy)ethylthioureas and their use as specific or selective agonists of xcex12B adrenergic receptors. More specifically the present invention relates to the above-noted compounds, pharmaceutical compositions containing these compounds as active ingredient for modulating the xcex12B adrenergic receptors, and even more specifically for utilizing these compounds and pharmaceutical compositions to alleviate chronic pain and allodynia.
2. Background Art
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors tend to bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The preferred binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into xcex11, xcex12, xcex21, and xcex22 subtypes. Functional differences between xcex11 and xcex12 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in published international patent application WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic receptors of the xcex11 subtype was reported. The xcex11/xcex12 selectivity of this compound was disclosed as being significant because agonist stimulation of the xcex12 receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the xcex12 receptor was said to increase secretion of these hormones. Thus, the use of non-selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, was said to be limited by their xcex12 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction). For a further general background on the xcex1-adrenergic receptors, the reader""s attention is directed to Robert R. Ruffolo, Jr., xcex1-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology., (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of xcex11/xcex12 subclassification, the molecular biology, signal transduction, agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting xcex1-adrenergic receptor affinity is explored.
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the xcex11 adrenoreceptors into (xcex11A, xcex11B, and xcex11D. Similarly, the xcex12 adrenoreceptors have also been classified xcex12A, xcex12B, and xcex12C receptors. Each xcex12 receptor subtype appears to exhibit its own pharmacological and tissue specificities. Compounds having a degree of specificity for one or more of these subtypes may be more specific therapeutic agents for a given indication than an xcex12 receptor pan-agonist (such as the drug clonidine) or a pan-antagonist.
Among other indications, such as the treatment of glaucoma, hypertension, sexual dysfunction, and depression, certain compounds having alpha 2 adrenergic receptor agonist activity are known analgesics. However, many compounds having such activity do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoreceptors. For example, many compounds found to be effective agents in the treatment of pain are frequently found to have undesirable side effects, such as causing hypotension and sedation at systemically effective doses. There is a need for new drugs that provide relief from pain without causing these undesirable side effects. Additionally, there is a need for agents which display activity against pain, particularly chronic pain, such as chronic neuropathic and visceral pain.
British Patent 1 499 485, published Feb. 1, 1978 describes certain thiocarbamide derivatives; some of these are said to be useful in the treatment of conditions such as hypertension, depression or pain.
Certain presently pending applications for patent owned by the the assignee as the present application describe phenylmethyl-(2hydroxy)ethylthioureas which have no significant cardiovascular or sedative effects and are useful for alleviating chronic pain and allodynia.
The present invention is directed to compounds having formula (i) and formula (ii) 
wherein the dotted line represents a bond, or absence of a bond with the provisos that only one dotted line represents a bond in the ring of formula (i) or of formula (ii);
R1 is H, or is absent when the carbon bearing the R1 is double bonded;
R2 is H, alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons; OH, O-alkyl where the alkyl group has 1 to 4 carbons, OCOR4 where R4 is alkyl of 1 to 4 carbons, F, Cl, Br or I;
m is an integer having the values of 1,2 or 3 with the proviso that when the compound is in accordance with formula (i) and m is 2 then the dotted line designated xcex3 represents absence of a bond, and
R3 is H, or R4CO, with the further provisos that when the compound is in accordance with formula (ii) then R2 is not OH, and when the compound is in accordance with formula (ii) and m is 1 then at least one R2 of the five-membered ring is not H.
In a second aspect the present invention is directed to pharmaceutical compositions containing as the active ingredient one or more compounds of formula (i) or of formula (ii), the compositions being utilized as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of xcex12B adrenergic receptors. The compositions containing the compounds of the invention are primarily, but not exclusively, used for alleviation of chronic pain and/or allodynia. The compounds have the advantageous property that they are specific or selective to xcex12B and/or xcex12C adrenergic receptors in preference over xcex12A adrenergic receptors, and as such have no or only minimal cardivascular and/or sedatory activity.